.beta.-Halolactic acids and glycidic acid are important as intermediates in synthesizing a variety of drugs, for example leukotriens, prostaglandins, .beta.-adrenal blockers and carnitine. In the past, most synthetic drugs were used in their racemic form, not in their optically active form. In recent years, however, several drugs have been found to be pharmacologically effective only in their optically active form while, when in racemic form, they are pharmacologically ineffective. Currently, there is an increasing tendency toward the synthesis of optically active compounds in the search for pharmacologically effective compounds. As is well known in the art, however, it is very difficult to synthesize optically active compounds by conventional methods of organic synthesis, which generally give only racemic products.
In producing optically active synthetic drugs, it is a frequent practice to produce or separate an optically active compound in an intermediate step of the synthesis and derive the final product drug therefrom. This is also the case with .beta.-halolactic acids and glycidic acid, which are important intermediates in drug synthesis, and attempts have been made to produce optically active .beta.-halolactic acids and optically active glycidic acid. Thus, for instance, in a process [process (a)] reported by Hirschbein et al. [B. L. Hirschbein and G. M. Whitesides: J. Am. Chem. Soc., 104, 4458 (1982)], optically active glycidic acid is synthesized by reducing chloropyruvic acid in the presence of lactate dehydrogenase and treating the resulting .beta.-chlorolactic acid with potassium hydroxide for cyclization.
In another process [process (b)] reported by Ohashi et al. [T. Ohashi and J. Hasegawa: Yuki Gosei Kagaku Kyokai Shi (J. Synth. Org. Chem., Japan), 45, 331 (1987); JP-A-61-268197 (the term "JP-A" as used herein means an "unexamined published Japanese patent application"); J. Ferment. Technol., 64, 251 (1986)], 3-chloro-1,2-propanediol is microbially oxidized, followed by cyclization by treatment with potassium hydroxide, as described by Hirschbein et al.
It is also generally known that 2-halo acid dehalogenase catalyzes the conversion of an L-2-halo acid to the corresponding D-hydroxy acid [J. Biol. Chem., 243, 428 (1968); J. Eur. Biochem., 21, 99 (1971); Agric, Biol. Chem., 46, 837 (1982); JP-A-57-125690 and JP-A-57-125691]. In particular, the production of D-lactic acid from L-chloropropionic acid can be an effective method of producing optically active lactic acid from an industrial viewpoint.
Another method known for the production of optically active lactic acid starts with racemic chloropropionic acid and uses 2-halo acid dehalogenase which acts on both L-2-halo acid and D-2-halo acid (JP-A-59-31690). It is unknown whether an .alpha.,.beta.-dihalopropionic acid, which is halogenated not only on the .alpha.-position carbon atom but also on the .beta.-position carbon atom, can undergo dehalogenation only on the .alpha.-position carbon atom.
The above process (a) is disadvantageous in that an expensive coenzyme, namely NADH, must be used. Therefore, that process cannot become a commercial method for synthesizing an optically active .beta.-halolactic acid or optically active glycidic acid. To overcome this drawback, a method which used glucose-6-phosphate dehydrogenase or, in other words, a coenzyme reproduction system in conjugation, has been proposed. However, this method has so far failed to produce satisfactory economic effects and, furthermore, is disadvantageous in that the two enzymes and the coenzyme NADH coexist in the reaction system, rendering the reaction system very complicated.
Process (b) does not involves the coenzyme regeneration problem but is disadvantageous in that the yield is as low as 10 to 28%.
In conclusion, none of the known processes or methods can be said to be a commercially advantageous way of producing an optically active .beta.-halolactic acid or optically active glycidic acid.
While, as mentioned above, it is known that 2-halo acid dehalogenase acts on 2-halo acids to cause the dehalogenation, the prior art teaches nothing about the selective dehalogenation of .alpha.,.beta.-dihalopropionic acids at the .alpha.-position.